Project Summary: Heart disease is a leading cause of non-communicable disease-related morbidity and mortality in the well-treated HIV population, and heart failure with preserved ejection fraction (HFpEF) is rising in prevalence. There are no FDA-approved therapeutics directed at HFpEF that effectively reduce morbidity and mortality in HIV or the general population, which highlights an expanding population of patients with a significant unmet clinical need. Early changes in myocardial structure and function are well-recognized among asymptomatic persons with HIV (PWH), affecting 50-60% of the population. The exact mechanism precipitating antecedent myocardial dysfunction, related to altered relaxation and increased stiffness and filling pressures of the left ventricle, and subsequent progression to symptomatic HFpEF in HIV is unclear. Myocardial inflammation and fibrosis are postulated to be substantial mediators of HFpEF and are mechanistically relevant among PWH whom demonstrate chronic systemic inflammation and immune activation and metabolic disease regardless of immunological control. Rigorous hormonal testing from our group among PWH show increased renin-angiotensin-aldosterone system (RAAS) activation is relation to reduced natriuretic peptide (NP) and increased inflammation and monocyte/macrophage activation. NPs have cardioprotective effects, and relatively reduced NPs could impair activities related to natriuresis, vasodilation, myocyte hypertrophy, and fibroblast proliferation, altering stability of the myocardium. We further postulate relatively reduced NP, a phenotype shown in highly metabolic groups and now demonstrated for the first time in HIV, may allow permissive RAAS activation leading to downstream inflammation and myocardial damage. We aim to investigate the cardiac phenotype associated with reduced NP among PWH compared to uninfected individuals utilizing advanced CV imaging techniques (cardiac MRI, cardiac TTE) and circulating myocardial biomarkers to comprehensively assess myocardial inflammation, structure, and function. This novel proposal represents a substantial departure from the typically well-studied HF patients with relatively higher NP and may uncover a large class of newly-identified inflammatory-prone or metabolically-deranged patients deserving of more clinical attention in the HF realm. We will also determine the effect of sacubitril/valsartan, a dual angiotensin II receptor antagonist and neprilysin inhibitor, vs. placebo on longitudinal changes in myocardial inflammation, structure and function among PWH in a 6-month randomized controlled trial. These studies apply a novel concept in studying PWH, among whom we postulate a therapy to simultaneously increase NP and decrease RAAS activation may be beneficial for heart disease based on unique RAAS-NP physiology in HIV. These studies led by an early stage investigator and team of experts in HIV-associated CVD, CV imaging, HFpEF phenotyping, CV biomarker science, and CV endocrinology will provide key insight on two neurohormonal systems critical to CV health, RAAS-NP, and test whether targeted manipulation of these systems can reduce subclinical HFpEF risk in HIV.